Dataset Information

Gefitinib exposure and occurrence of interstitial lung disease in Japanese patients with non-small-cell lung cancer.

ABSTRACT:

Purpose

A prospective, multicenter, large-scale cohort with a nested case-control study (NCT00252759) was conducted to identify and quantify risk factors for interstitial lung disease (ILD) in Japanese patients with non-small-cell lung cancer who received gefitinib. This study reports the association between gefitinib exposure and the occurrence of ILD.

Methods

A total of 1891 gefitinib plasma concentrations from 336 patients were measured after first dose, at steady state, and at time of ILD occurrence. Influences of demographic and pathophysiological factors on pharmacokinetics were investigated by non-linear mixed-effect modeling. The exposure to gefitinib was compared between patients without and with ILD occurrence to explore risks associated with gefitinib-induced ILD. Intra-patient comparison of exposure was also conducted between times at ILD development and normal states.

Results

In the population pharmacokinetic analysis for gefitinib, α₁-acid glycoprotein (AGP), age, body weight, and concomitant use of cytochrome P450 3A4 inducers were significant covariates on oral clearance (CL/F). AGP and body weight were also identified as factors affecting the volume of distribution. CL/F was significantly lower at the time of ILD occurrence than normal states. Patients who developed ILD tended to show higher exposure to gefitinib than those without ILD; however, these differences were not statistically significant. On the other hand, exposure at the time of ILD occurrence was significantly elevated compared to the time of normal state within the same patients.

Conclusions

Significant elevation of exposure of gefitinib was observed at the time of ILD occurrence, suggesting reduction of CL/F could be associated with ILD-induced AGP elevation. Increase in exposure of gefitinib is unlikely to be a robust predictor of ILD and does not warrant any dose modifications.

SUBMITTER: Kawata T

PROVIDER: S-EPMC6458983 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundInterstitial lung disease (ILD) in patients with non-small cell lung cancer (NSCLC) worsens the prognosis for overall survival (OS) due to chemotherapy-triggered acute exacerbation (AE)-ILD. The Glasgow Prognostic Score (GPS), which is based on serum C-reactive protein and albumin levels, has been suggested as a reliable prognostic tool for mortality in cancer patients, including NSCLC. In this study, we investigated whether GPS is a predictor for chemotherapy-triggered AE-ILD and the prognosis in patients with NSCLC and pre-existing ILD.MethodsWe conducted a retrospective review on 56 NSCLC and ILD patients at our hospital who received platinum agent-based treatment as first-line chemotherapy between June 2010 and May 2019. We categorized these patients according to their GPS (0-2) and compared the incidence of chemotherapy-triggered AE-ILD and OS.ResultsThe GPS 0, 1, and 2 groups included 31, 16, and nine patients, respectively, out of 56. A total of 12 (21.4%) patients showed chemotherapy-triggered AE-ILD. The median OS was at 11.5 months (95% confidence interval: 8.0-15.1). The incidence of chemotherapy-triggered AE-ILD within the first year of chemotherapy in the GPS 0, 1, and 2 groups was three (9.6%), four (25.0%), and five (55.5%), and the median OS time was 16.9, 9.8 and 7.6 months, respectively. Univariate and multivariate analyses indicated that only GPS 2 could predict both chemotherapy-triggered AE-ILD and OS (P < 0.05).ConclusionsGPS assessment of patients with NSCLC and pre-existing ILD is a valuable prognostic tool for predicting chemotherapy-triggered AE-ILD and OS.Key pointsSIGNIFICANT FINDINGS OF THE STUDY: We found that GPS 2 was an independent risk factor for chemotherapy-triggered AE-ILD and prognosis in patients with ILD associated with NSCLC.What this study addsGPS may potentially enable the discrimination of patients tolerant of chemotherapy from those at an increased risk of AE-ILD and predict the prognosis in patients with NSCLC and ILD receiving chemotherapy.